11056-06-7BleomycinBleo
Bleocin
Blenamax
Bleo-Kyowa
Bleomycins
NSC 125066
DTXSID1030862CHEBI:3815collagenGO:0032964collagen biosynthetic process1increasedCarbon nanotubes2017-08-09T08:01:552017-08-09T08:03:46Bleomycin<p><strong>Bleomycin</strong> is a potent anti-tumour drug, routinely used for treating various types of human cancers (Umezawa et al., 1967; Adamson, 1976). Lung injury and lung fibrosis are the major adverse effects of this drug in humans (Hay J et al., 1991). Bleomycin is shown to induce lung fibrosis in experimental animals - in dogs (Fleischman et al., 1971), mice (Adamson IY and Bowden DH, 1974), hamsters (Snider GL et al., 1978) and is widely used as a model chemical to study the mechanisms of fibrosis in humans (reviewed in <strong>Moeller</strong> et al., <strong>2008;</strong> Gilhodes et al., 2017).</p>
<ol>
<li>Adamson, I. (1976). Pulmonary Toxicity of Bleomycin. Environmental Health Perspectives, 16, p.119.</li>
<li>Adamson, IYR. and Bowden, DH. (1974). The Pathogenesis of Bleomycin-Induced Pulmonary Fibrosis in Mice. <em>The American Journal of Pathology</em>. 77(2), pp185-198.</li>
<li>Fleischman, R., Baker, J., Thompson, G., Schaeppi, U., Illievski, V., Cooney, D. and Davis, R. (1971). Bleomycin-induced interstitial pneumonia in dogs. Thorax, 26(6), pp.675-682.</li>
<li>Gilhodes, J., Julé, Y., Kreuz, S., Stierstorfer, B., Stiller, D. and Wollin, L. (2017). Quantification of Pulmonary Fibrosis in a Bleomycin Mouse Model Using Automated Histological Image Analysis. PLOS ONE, 12(1), p.e0170561.</li>
<li>Hay, J., Shahzeidi, S. and Laurent, G. (1991). Mechanisms of bleomycin-induced lung damage. Archives of Toxicology, 65(2), pp.81-94.</li>
<li>Moeller, A., Ask, K., Warburton, D., Gauldie, J. and Kolb, M. (2008). The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis?. The International Journal of Biochemistry & Cell Biology, 40(3), pp.362-382.</li>
<li>Snider GL., Celli, BR., Goldstein, RH., O'Brien, JJ. and Lucey, EC. (1978). Chronic interstitial pulmonary fibrosis produced in hamsters by endotracheal bleomycin. Lung volumes, volume-pressure relations, carbon monoxide uptake, and arterial blood gas studied. <em>Am Rev Respir Dis.</em> Feb; 117(2). pp289-97.</li>
<li>Umezawa, H., Ishizuka, M., Maeda, K. and Takeuchi, T. (1967). Studies on bleomycin. Cancer, 20(5), pp.891-895.</li>
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2018-01-01T16:45:532019-10-29T13:08:19Carbon nanotubes, Multi-walled carbon nanotubes, single-walled carbon nanotubes, carbon nanofibres<p> </p>
<p>Julie Mullera, Franc¸ois Huauxa, Nicolas Moreaub, Pierre Missona, Jean-Franc¸ois Heiliera,</p>
<p>Monique Delosc, Mohammed Arrasa, Antonio Fonsecab, Janos B. Nagyb, Dominique Lison</p>
<p>Julie Mullera, Franc¸ois Huauxa, Nicolas Moreaub, Pierre Missona, Jean-Franc¸ois Heiliera,</p>
<p>Monique Delosc, Mohammed Arrasa, Antonio Fonsecab, Janos B. Nagyb, Dominique Lison</p>
2018-01-01T17:51:042018-01-01T17:52:30WCS_9606humansWCS_9606human10116Rattus norvegicus10090mouse10116ratIncrease, Differentiation of fibroblastsDifferentiation of fibroblastsCellular2017-07-26T19:10:082017-07-26T19:10:08Induction, Epithelial Mesenchymal TransitionEMTCellular<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Process:transition of epithelial cells to mesenchymal Object: epithelial cells </span></span></p>
<p><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif"> Action:increased</span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Process:transition of epithelial cells to mesenchymal Object: epithelial cells </span></span></p>
<p><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif"> Action:increased</span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="color:black">Biological state</span></strong></span></span></p>
<p> </p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">An epithelial-mesenchymal transition (EMT) is a biologic process in which epithelial cells are polarized, interact through their basal surface with basement membrane, and undergo biochemical changes to assume a mesenchymal cell phenotype. </span></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">This phenotypic transformation has various characters such as enhanced migratory capacity, high invasiveness, elevated resistance to apoptosis, and greatly increased production of ECM components (Kalluri, R., and Neilson, E.G. 2003). The completion of an EMT is signalled by the degradation of the underlying basement membrane and the formation of a mesenchymal cell that can migrate away from the epithelial layer in which it originated.</span></span></span></p>
<p> </p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black"> EMT has a number of distinct molecular processes like activation of transcription factors, expression of specific cell surface proteins, reorganization and expression of cytoskeletal proteins, production of ECM-degrading enzymes, and changes in the expression of specific microRNAs. These factors are used as biomarkers to demonstrate the passage of a cell through an EMT. </span></span></span></p>
<p> </p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="color:black">Biological compartment </span></strong></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Cellular</span></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="color:black">Role in General Biology:</span></strong></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Excessive proliferation of epithelial cells and angiogenesis mark the initiation and early growth of primary epithelial cancers. (Hanahan, D., and Weinberg, R.A. 2000). The subsequent acquisition of invasiveness, initially manifest by invasion through the basement membrane, is thought to herald the onset of the last stages of the multi-step process that leads eventually to metastatic dissemination, with life-threatening consequences. There has been an intense research going on in the genetic controls and biochemical mechanisms underlying the acquisition of the invasive phenotype and the subsequent systemic spread of the cancer cell. Activation of an EMT program has been proposed as the critical mechanism for the acquisition of malignant phenotypes by epithelial cancer cells (Thiery, J.P. 2002).</span></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black"> Pre-clinical experiments such as mice models and cell culture experiments has demonstrated that carcinoma cells can acquire a mesenchymal phenotype and express mesenchymal markers such as </span><span style="color:black">α</span><span style="color:black">-SMA, FSP1, vimentin, and desmin (Yang, J., and Weinberg, R.A. 2008). These cells are seen at the invasive front of primary tumors and are considered to be the cells that eventually enter into subsequent steps of the invasion-metastasis cascade, i.e., intravasation, transport through the circulation, extravasation, formation of micro metastases, and ultimately colonization (the growth of small colonies into macroscopic metastases) (Thiery, J.P. 2002, Fidler, I.J., and Poste, G. 2008, Brabletz, T., et al. 2001).</span></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">An apparent paradox comes from the observation that the EMT-derived migratory cancer cells typically establish secondary colonies at distant sites that resemble, at the histopathological level, the primary tumor from which they arose; accordingly, they no longer exhibit the mesenchymal phenotypes ascribed to metastasizing carcinoma cells. Reconciling this behaviour with the proposed role of EMT as a facilitator of metastatic dissemination requires the additional notion that metastasizing cancer cells must shed their mesenchymal phenotype via a MET during the course of secondary tumor formation (Zeisberg, M et al 2005). The tendency of disseminated cancer cells to undergo EMT likely reflects the local microenvironments that they encounter after extravasation into the parenchyma of a distant organ, quite possibly the absence of the heterotypic signals they experienced in the primary tumor that were responsible for inducing the EMT in the first place (Thiery, J.P. 2002, Jechlinger, M et al 2002, Bissell, M.J et al 2002). These evidences indicate that induction of an EMT is likely to be a centrally important mechanism for the progression of carcinomas to a metastatic stage and implicates MET during the subsequent colonization process. However, many steps of this mechanistic model still require direct experimental validation. It remains unclear at present whether these phenomena and molecular mechanisms relate to and explain the metastatic dissemination of non-epithelial cancer cells.</span></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">The entire spectrum of signaling agents that contribute to EMTs of carcinoma cells remains unclear. One theory suggests that the genetic and epigenetic alterations undergone by cancer cells during the course of primary tumor formation render them especially responsive to EMT-inducing heterotypic signals originating in the tumor-associated stroma. Oncogenes induce senescence, and recent studies suggest that cancer cell EMTs may also play a role in preventing senescence induced by oncogenes, thereby facilitating subsequent aggressive dissemination (Smit, M.A., and Peeper, D.S. 2008, Ansieau, S., et al. 2008, Weinberg, R.A. 2008). In the case of many carcinomas, EMT-inducing signals emanating from the tumor-associated stroma, notably HGF, EGF, PDGF, and TGF-</span><span style="color:black">β</span><span style="color:black">, appear to be responsible for the induction or functional activation in cancer cells of a series of EMT-inducing transcription factors, notably Snail, Slug, zinc finger E-box binding homeobox 1 (ZEB1), Twist, Goosecoid, and FOXC2 (Thiery, J.P. 2002, Jechlinger, M et al 2002, Shi, Y., and Massague, J. 2003, Niessen, K., et al. 2008, Medici, D et al 2008, Kokudo, T., et al. 2008). Once expressed and activated, each of these transcription factors can act pleiotropically to choreograph the complex EMT program, more often than not with the help of other members of this cohort of transcription factors. The actual implementation by these cells of their EMT program depends on a series of intracellular signaling networks involving, among other signal- transducing proteins, ERK, MAPK, PI3K, Akt, Smads, RhoB, </span><span style="color:black">β</span><span style="color:black">-catenin, lymphoid enhancer binding factor (LEF), Ras, and c-Fos as well as cell surface proteins such as </span><span style="color:black">β</span><span style="color:black">4 integrins, </span><span style="color:black">α</span><span style="color:black">5</span><span style="color:black">β</span><span style="color:black">1 integrin, and </span><span style="color:black">α</span><span style="color:black">V</span><span style="color:black">β</span><span style="color:black">6 integrin (Tse, J.C., and Kalluri, R. 2007). Activation of EMT programs is also facilitated by the disruption of cell-cell adherens junctions and the cell-ECM adhesions mediated by integrins (Yang, J., and Weinberg, R.A. 2008, Weinberg, R.A. 2008, Gupta, P.B et al 2005, Yang, J et al 2006, Mani, S.A., et al. 2007, Mani, S.A., et al. 2008, Hartwell, K.A., et al. 2006, Taki, M et al 2006)..</span></span></span></p>
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<p>Loss of <a href="https://en.wikipedia.org/wiki/E-cadherin">E-cadherin</a> and cell polarity is considered to be a fundamental event in epithelial-mesenchymal transition. The simultaneous expression of epithelial (e.g. E-cadherin) and mesenchymal markers (e.g. N-cadherin and vimentin) within the airway epithelium are indicative for ongoing transition (Borthwick et al. 2009, 2010).</p>
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<p style="text-align:justify"> </p>
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<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:155px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Method/ measurement referenc</span></span></p>
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<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Reliability</span></span></p>
<p style="text-align:justify"> </p>
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<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:68px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Strength of evidence</span></span></p>
<p style="text-align:justify"> </p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:63px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Assay fit for purpose</span></span></p>
<p style="text-align:justify"> </p>
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<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:102px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Repeatability/ reproducibility</span></span></p>
<p style="text-align:justify"> </p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:67px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Direct measure</span></span></p>
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<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Human cell line</span></span></p>
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<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:155px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">qRT-PCR,cell viability assay,</span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Western blotting,EdU incorporation assay</span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:73px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">+</span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:68px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Strong</span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:63px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Yes </span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:102px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Yes</span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:67px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Yes </span></span></p>
</td>
</tr>
<tr>
<td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:58px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Human</span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:155px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">IHC,micro array,qPCR, SNP array</span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:73px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">+</span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:68px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Moderate</span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:63px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Yes </span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:102px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Yes</span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:67px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Yes </span></span></p>
</td>
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<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Regulation of miRNA expression by DNA replication,damage and repair responses,transcription and translation has been proved in animals like mice,canine and cell line experiments.</span></span></p>
Not SpecifiedUnspecificNot SpecifiedNot Otherwise SpecifiedHigh<p>Borthwick, L. A., Parker, S. M., Brougham, K. A., Johnson, G. E., Gorowiec, M. R., Ward, C., … Fisher, A. J. (2009). Epithelial to mesenchymal transition (EMT) and airway remodelling after human lung transplantation. <em>Thorax</em>, <em>64</em>(9), 770–777. <a href="https://doi.org/10.1136/thx.2008.104133"><u>https://doi.org/10.1136/thx.2008.104133</u></a></p>
<p>Borthwick, L. A., McIlroy, E. I., Gorowiec, M. R., Brodlie, M., Johnson, G. E., Ward, C., … Fisher, A. J. (2010). Inflammation and epithelial to mesenchymal transition in lung transplant recipients: Role in dysregulated epithelial wound repair. <em>American Journal of Transplantation</em>, <em>10</em>(3), 498–509. <a href="https://doi.org/10.1111/j.1600-6143.2009.02953.x"><u>https://doi.org/10.1111/j.1600-6143.2009.02953.x</u></a></p>
<p>Al Saleh, S., Al Mulla, F., & Luqmani, Y. A. (2011). Estrogen receptor silencing induces epithelial to mesenchymal transition in human breast cancer cells. PloS one, 6(6), e20610.</p>
<p>Bissell, M. J., Radisky, D. C., Rizki, A., Weaver, V. M., & Petersen, O. W. (2002). The organizing principle: microenvironmental influences in the normal and malignant breast. Differentiation, 70(9-10), 537-546.</p>
<p>Bouris, P., Skandalis, S. S., Piperigkou, Z., Afratis, N., Karamanou, K., Aletras, A. J., ... & Karamanos, N. K. (2015). Estrogen receptor alpha mediates epithelial to mesenchymal transition, expression of specific matrix effectors and functional properties of breast cancer cells. Matrix Biology, 43, 42-60.</p>
<p> Brabletz, T., Jung, A., Reu, S., Porzner, M., Hlubek, F., Kunz-Schughart, L. A., ... & Kirchner, T. (2001). Variable β-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proceedings of the National Academy of Sciences, 98(18), 10356-10361.</p>
<p>Brabletz, T., Jung, A., Reu, S., Porzner, M., Hlubek, F., Kunz-Schughart, L. A., ... & Kirchner, T. (2001). Variable β-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proceedings of the National Academy of Sciences, 98(18), 10356-10361.</p>
<p>idler, I. J., & Poste, G. (2008). The “seed and soil” hypothesis revisited. The lancet oncology, 9(8), 808.</p>
<p>Gupta, P. B., Mani, S., Yang, J., Hartwell, K., & Weinberg, R. A. (2005, January). The evolving portrait of cancer metastasis. In Cold Spring Harbor symposia on quantitative biology (Vol. 70, pp. 291-297). Cold Spring Harbor Laboratory Press.</p>
<p>Hanahan, D., and Weinberg, R.A. (2000). The hall- marks of cancer. Cell. 100:57–70.</p>
<p>Hartwell, K. A., Muir, B., Reinhardt, F., Carpenter, A. E., Sgroi, D. C., & Weinberg, R. A. (2006). The Spemann organizer gene, Goosecoid, promotes tumor metastasis. Proceedings of the National Academy of Sciences, 103(50), 18969-18974.</p>
<p>Jechlinger, M., Grünert, S., & Beug, H. (2002). Mechanisms in epithelial plasticity and metastasis: insights from 3D cultures and expression profiling. Journal of mammary gland biology and neoplasia, 7(4), 415-432.</p>
<p> Kalluri, R., & Neilson, E. G. (2003). Epithelial-mesenchymal transition and its implications for fibrosis. The Journal of clinical investigation, 112(12), 1776-1784.</p>
<p>Kokudo, T., Suzuki, Y., Yoshimatsu, Y., Yamazaki, T., Watabe, T., & Miyazono, K. (2008). Snail is required for TGFβ-induced endothelial-mesenchymal transition of embryonic stem cell-derived endothelial cells. Journal of cell science, 121(20), 3317-3324.<br />
Lin, H. Y., Liang, Y. K., Dou, X. W., Chen, C. F., Wei, X. L., Zeng, D., ... & Zhang, G. J. (2018). Notch3 inhibits epithelial–mesenchymal transition in breast cancer via a novel mechanism, upregulation of GATA-3 expression. Oncogenesis, 7(8), 1-15.</p>
<p>Liu, Y., Liu, R., Fu, P., Du, F., Hong, Y., Yao, M., ... & Zheng, S. (2015). N1-Guanyl-1, 7-diaminoheptane sensitizes estrogen receptor negative breast cancer cells to doxorubicin by preventing epithelial-mesenchymal transition through inhibition of eukaryotic translation initiation factor 5A2 activation. Cellular Physiology and Biochemistry, 36(6), 2494-2503.</p>
<p>Mani, S. A., Yang, J., Brooks, M., Schwaninger, G., Zhou, A., Miura, N., ... & Weinberg, R. A. (2007). Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. Proceedings of the National Academy of Sciences, 104(24), 10069-10074.</p>
<p>Mani, S. A., Guo, W., Liao, M. J., Eaton, E. N., Ayyanan, A., Zhou, A. Y., ... & Weinberg, R. A. (2008). The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell, 133(4), 704-715.<br />
Medici, D., Hay, E. D., & Olsen, B. R. (2008). Snail and Slug promote epithelial-mesenchymal transition through β-catenin–T-cell factor-4-dependent expression of transforming growth factor-β3. Molecular biology of the cell, 19(11), 4875-4887.</p>
<p>Niessen, K., Fu, Y., Chang, L., Hoodless, P. A., McFadden, D., & Karsan, A. (2008). Slug is a direct Notch target required for initiation of cardiac cushion cellularization. The Journal of cell biology, 182(2), 315-325.</p>
<p>Shi, Y., & Massagué, J. (2003). Mechanisms of TGF-β signaling from cell membrane to the nucleus. cell, 113(6), 685-700.</p>
<p>Smit, M. A., & Peeper, D. S. (2008). Deregulating EMT and senescence: double impact by a single twist. Cancer cell, 14(1), 5-7.</p>
<p>Taki, M., Verschueren, K., Yokoyama, K., Nagayama, M., & Kamata, N. (2006). Involvement of Ets-1 transcription factor in inducing matrix metalloproteinase-2 expression by epithelial-mesenchymal transition in human squamous carcinoma cells. International journal of oncology, 28(2), 487-496.</p>
<p>Thiery, J. P. (2002). Epithelial–mesenchymal transitions in tumour progression. Nature reviews cancer, 2(6), 442-454.</p>
<p>Tse, J. C., & Kalluri, R. (2007). Mechanisms of metastasis: epithelial‐to‐mesenchymal transition and contribution of tumor microenvironment. Journal of cellular biochemistry, 101(4), 816-829.</p>
<p>Weinberg, R. A. (2008). Twisted epithelial–mesenchymal transition blocks senescence. Nature cell biology, 10(9), 1021-1023.</p>
<p>Wik, E., Ræder, M. B., Krakstad, C., Trovik, J., Birkeland, E., Hoivik, E. A., ... & Salvesen, H. B. (2013). Lack of estrogen receptor-α is associated with epithelial–mesenchymal transition and PI3K alterations in endometrial carcinoma. Clinical Cancer Research, 19(5), 1094-1105.</p>
<p>Yang, J., & Weinberg, R. A. (2008). Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Developmental cell, 14(6), 818-829.</p>
<p>Yang, J., Mani, S. A., & Weinberg, R. A. (2006). Exploring a new twist on tumor metastasis. Cancer research, 66(9), 4549-4552.</p>
<p>Ye, Y., Xiao, Y., Wang, W., Yearsley, K., Gao, J. X., Shetuni, B., & Barsky, S. H. (2010). ERα signaling through slug regulates E-cadherin and EMT. Oncogene, 29(10), 1451-1462.</p>
<p>Zeisberg, M., Shah, A. A., & Kalluri, R. (2005). Bone morphogenic protein-7 induces mesenchymal to epithelial transition in adult renal fibroblasts and facilitates regeneration of injured kidney. Journal of Biological Chemistry, 280(9), 8094-8100.</p>
<p>Zeng, Q., Zhang, P., Wu, Z., Xue, P., Lu, D., Ye, Z., ... & Yan, X. (2014). Quantitative proteomics reveals ER-α involvement in CD146-induced epithelial-mesenchymal transition in breast cancer cells. Journal of proteomics, 103, 153-169. <br />
</p>
<p> </p>
<ul>
<li><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt"><span style="background-color:white"><span style="font-family:"Arial",sans-serif"><span style="color:#222222">Zeng, Q., Zhang, P., Wu, Z., Xue, P., Lu, D., Ye, Z., ... & Yan, X. (2014). Quantitative proteomics reveals ER-α involvement in CD146-induced epithelial-mesenchymal transition in breast cancer cells. <em>Journal of proteomics</em>, <em>103</em>, 153-169.</span></span></span></span> </span></span></li>
</ul>
2017-07-26T19:11:332023-08-27T07:39:03Accumulation, CollagenAccumulation, CollagenTissue<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Collagen is mostly found in fibrous tissues such as tendons, ligaments and skin. It is also abundant in corneas, cartilage, bones, blood vessels, the gut, intervertebral discs, and the dentin in teeth. In muscle tissue, it serves as a major component of the endomysium. Collagen is the main structural protein in the extracellular space in the various connective tissues, making up from 25% to 35% of the whole-body protein content. In normal tissues, collagen provides strength, integrity, and structure. When tissues are disrupted following injury, collagen is needed to repair the defect. If too much collagen is deposited, normal anatomical structure is lost, function is compromised, and fibrosis results.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">The fibroblast is the most common collagen producing cell. Collagen-producing cells may also arise from the process of transition of differentiated epithelial cells into mesenchymal cells. This has been observed e.g. during renal fibrosis (transformation of tubular epithelial cells into fibroblasts) and in liver injury (transdifferentiation of hepatocytes and cholangiocytes into fibroblasts) (Henderson and Iredale, 2007)<sup>.</sup></span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">There are close to 20 different types of collagen found with the predominant form being type I collagen. This fibrillar form of collagen represents over 90 percent of our total collagen and is composed of three very long protein chains which are wrapped around each other to form a triple helical structure called a collagen monomer. Collagen is produced initially as a larger precursor molecule called procollagen. As the procollagen is secreted from the cell, procollagen proteinases remove the extension peptides from the ends of the molecule. The processed molecule is referred to as collagen and is involved in fiber formation. In the extracellular spaces the triple helical collagen molecules line up and begin to form fibrils and then fibers. Formation of stable crosslinks within and between the molecules is promoted by the enzyme lysyl oxidase and gives the collagen fibers tremendous strength (Diegelmann,2001)<sup>.</sup> The overall amount of collagen deposited by fibroblasts is a regulated balance between collagen synthesis and collagen catabolism. Disturbance of this balance leads to changes in the amount and composition of collagen. Changes in the composition of the extracellular matrix initiate positive feedback pathways that increase collagen production.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Normally, collagen in connective tissues has a slow turn over; degradating enzymes are collagenases, belonging to the family of matrix metalloproteinases. Other cells that can synthesize and release collagenase are macrophages, neutrophils, osteoclasts, and tumor cells (Di Lullo et al., 2002; Kivirikko and Risteli, 1976; Miller and Gay, 1987; Prockop and Kivirikko, 1995).</span></span></p>
<p> </p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Determination of the amount of collagen produced <em>in vitro</em> can be done in a variety of ways ranging from simple colorimetric assays to elaborate chromatographic procedures using radioactive and non-radioactive material. What most of these procedures have in common is the need to destroy the cell layer to obtain solubilized collagen from the pericellular matrix. Rishikof et al. describe several methods to assess the <em>in vitro</em> production of type I collagen: Western immunoblotting of intact alpha1(I) collagen using antibodies directed to alpha1(I) collagen amino and carboxyl propeptides, the measurement of alpha1(I) collagen mRNA levels using real-time polymerase chain reaction, and methods to determine the transcriptional regulation of alpha1(I) collagen using a nuclear run-on assay (Rishikof et al., 2005). </span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Histological staining with stains such as Masson Trichrome, Picro-sirius red are used to identify the tissue/cellular distribution of collagen, which can be quantified using morphometric analysis both <em>in vivo</em> and <em>in vitro</em>. The assays are routinely used and are quantitative.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><em><strong>Sircol Collagen Assay for collagen quantification:</strong></em></span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">The Serius dye has been used for many decades to detect collagen in histology samples. The Serius Red F3BA selectively binds to collagen and the signal can be read at 540 nm (Chen and Raghunath, 2009; Nikota et al., 2017).</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><em><strong>Hydroxyproline assay:</strong></em></span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Hydroxyproline is a non-proteinogenic amino acid formed by the prolyl-4-hydroxylase. Hydroxyproline is only found in collagen and thus, it serves as a direct measure of the amount of collagen present in cells or tissues. Colorimetric methods are readily available and have been extensively used to quantify collagen using this assay (Chen and Raghunath, 2009; Nikota et al., 2017).</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong><em>Ex vivo precision cut tissue slices</em></strong></span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Precision cut tissue slices mimic the whole organ response and allow histological assessment, an endpoint of interest in regulatory decision making. While this technique uses animals, the number of animals required to conduct a dose-response study can be reduced to 1/4<sup>th</sup> of what will be used in whole animal exposure studies (Rahman et al., 2020). </span></span></p>
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</span></span></pre>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Humans: Bataller and Brenner, 2005; Decaris et al., 2015. </span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Mice: Dalton et al., 2009; Leung et al., 2008; Nan et al., 2013.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Rats: Hamdy and El-Demerdash, 2012; Li et al., 2012; Luckey and Petersen, 2001; Natajaran et al., 2006.</span></span></p>
<p> </p>
UBERON:0002384connective tissueNot SpecifiedUnspecificNot SpecifiedAll life stagesHighHighHigh<ol>
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<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005 Feb;115(2):209-18. doi: 10.1172/JCI24282. </span></span></p>
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<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Chen CZ, Raghunath M. Focus on collagen: in vitro systems to study fibrogenesis and antifibrosis state of the art. Fibrogenesis Tissue Repair. 2009 Dec 15;2:7. doi: 10.1186/1755-1536-2-7. </span></span></p>
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<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Dalton SR, Lee SM, King RN, Nanji AA, Kharbanda KK, Casey CA, McVicker BL. Carbon tetrachloride-induced liver damage in asialoglycoprotein receptor-deficient mice. Biochem Pharmacol. 2009 Apr 1;77(7):1283-90. doi: 10.1016/j.bcp.2008.12.023. </span></span></p>
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<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Decaris ML, Emson CL, Li K, Gatmaitan M, Luo F, Cattin J, Nakamura C, Holmes WE, Angel TE, Peters MG, Turner SM, Hellerstein MK. Turnover rates of hepatic collagen and circulating collagen-associated proteins in humans with chronic liver disease. PLoS One. 2015 Apr 24;10(4):e0123311. doi: 10.1371/journal.pone.0123311.</span></span></p>
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<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Di Lullo GA, Sweeney SM, Korkko J, Ala-Kokko L, San Antonio JD. Mapping the ligand-binding sites and disease-associated mutations on the most abundant protein in the human, type I collagen. J Biol Chem. 2002 Feb 8;277(6):4223-31. doi: 10.1074/jbc.M110709200.</span></span></p>
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<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Diegelmann R. Collagen Metabolism. Wounds. 2001;13:177-82. Available at www.medscape.com/viewarticle/423231 (accessed on 20 January 2016).</span></span></p>
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<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Hamdy N, El-Demerdash E. New therapeutic aspect for carvedilol: antifibrotic effects of carvedilol in chronic carbon tetrachloride-induced liver damage. Toxicol Appl Pharmacol. 2012 Jun 15;261(3):292-9. doi: 10.1016/j.taap.2012.04.012. </span></span></p>
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<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Henderson NC, Iredale JP. Liver fibrosis: cellular mechanisms of progression and resolution. Clin Sci (Lond). 2007 Mar;112(5):265-80. doi: 10.1042/CS20060242.</span></span></p>
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<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Kivirikko KI, Risteli L. Biosynthesis of collagen and its alterations in pathological states. Med Biol. 1976 Jun;54(3):159-86.</span></span></p>
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<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Leung TM, Tipoe GL, Liong EC, Lau TY, Fung ML, Nanji AA. Endothelial nitric oxide synthase is a critical factor in experimental liver fibrosis. Int J Exp Pathol. 2008 Aug;89(4):241-50. doi: 10.1111/j.1365-2613.2008.00590.x. </span></span></p>
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<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Li L, Hu Z, Li W, Hu M, Ran J, Chen P, Sun Q. Establishment of a standardized liver fibrosis model with different pathological stages in rats. Gastroenterol Res Pract. 2012;2012:560345. doi: 10.1155/2012/560345. </span></span></p>
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<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Luckey SW, Petersen DR. Activation of Kupffer cells during the course of carbon tetrachloride-induced liver injury and fibrosis in rats. Exp Mol Pathol. 2001 Dec;71(3):226-40. doi: 10.1006/exmp.2001.2399.</span></span></p>
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<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Miller EJ, Gay S. The collagens: an overview and update. Methods Enzymol. 1987;144:3-41. doi: 10.1016/0076-6879(87)44170-0. </span></span></p>
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<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Nan YM, Kong LB, Ren WG, Wang RQ, Du JH, Li WC, Zhao SX, Zhang YG, Wu WJ, Di HL, Li Y, Yu J. Activation of peroxisome proliferator activated receptor alpha ameliorates ethanol mediated liver fibrosis in mice. Lipids Health Dis. 2013 Feb 6;12:11. doi: 10.1186/1476-511X-12-11.</span></span></p>
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<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Natarajan SK, Thomas S, Ramamoorthy P, Basivireddy J, Pulimood AB, Ramachandran A, Balasubramanian KA. Oxidative stress in the development of liver cirrhosis: a comparison of two different experimental models. J Gastroenterol Hepatol. 2006 Jun;21(6):947-57. doi: 10.1111/j.1440-1746.2006.04231.x.</span></span></p>
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<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Nikota J, Banville A, Goodwin LR, Wu D, Williams A, Yauk CL, Wallin H, Vogel U, Halappanavar S. Stat-6 signaling pathway and not Interleukin-1 mediates multi-walled carbon nanotube-induced lung fibrosis in mice: insights from an adverse outcome pathway framework. Part Fibre Toxicol. 2017 Sep 13;14(1):37. doi: 10.1186/s12989-017-0218-0. </span></span></p>
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<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Prockop DJ, Kivirikko KI. Collagens: molecular biology, diseases, and potentials for therapy. Annu Rev Biochem. 1995;64:403-34. doi: 10.1146/annurev.bi.64.070195.002155. </span></span></p>
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<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Rahman L, Williams A, Gelda K, Nikota J, Wu D, Vogel U, Halappanavar S. 21st Century Tools for Nanotoxicology: Transcriptomic Biomarker Panel and Precision-Cut Lung Slice Organ Mimic System for the Assessment of Nanomaterial-Induced Lung Fibrosis. Small. 2020 Sep;16(36):e2000272. doi: 10.1002/smll.202000272.</span></span></p>
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<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Rishikof DC, Kuang PP, Subramanian M, Goldstein RH. Methods for measuring type I collagen synthesis in vitro. Methods Mol Med. 2005;117:129-40. doi: 10.1385/1-59259-940-0:129. </span></span></p>
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2016-11-29T18:41:222023-05-17T15:55:30Pulmonary fibrosisPulmonary fibrosisOrgan<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Pulmonary fibrosis is broadly defined as the thickening or scarring of lung tissue, due to excessive deposition of extracellular matrix. In the normal human lung, the nasopharynx and the conducting airways are mainly covered by epithelium composed of ciliated, mucous secreting cells in direct contact with the basement membrane with submucosal glands containing goblet, duct, and serous cells also contributing to the fluid balance and mucous production (Koval and Sidhaye, 2017). Within this epithelium, basal cells are found which are stimulated to proliferate and differentiate in response to injury (Koval and Sidhaye, 2017). Further down the lung, in the terminal bronchiole region, the epithelium does not contain submucosal glands, but instead contains club cells which produce pulmonary surfactant and can differentiate into bronchiolar or alveolar epithelial cells (AECs). Finally, in the terminal airspaces, the epithelium is made up entirely of type I and type II AECs. In between the two adjacent alveoli are two layers of alveolar epithelium resting on basement membrane, which consists of interstitial space, pulmonary capillaries, elastin and collagen fibres. Thus, the alveolar capillary membrane (ACM), where gas exchange takes place, is made up of the alveolar epithelium and alveolar endothelium (Gracey et al, 1968). In pulmonary fibrosis, damage to the pulmonary epithelium results in excessive deposition of collagen by constitutively activated myofibroblasts during the wound healing response. This causes a pronounced decrease in the number of capillaries within the alveolar septa with asymmetric deposition of collagen and cells between part of the surface of a capillary and the nearby alveolar lining. In areas where capillaries are not present, the ACM is occupied with collagen and cells. </span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><em>In vivo</em>, histopathological analysis is used for assessing fibrotic lung disease. Morphometric analysis of the diseased area versus total lung area is used to quantitatively stage the fibrotic disease. Although, some inconsistencies can be introduced during the analysis due to the experience of the individual scoring the disease, the histological stain, etc., a numerical scale with grades from 0 to 8, originally developed by Ashcroft et al., 1988 is assigned to indicate the amount of fibrotic tissue in histological samples. This scale is applied to diagnose lung fibrosis in both human and animal samples. Modifications to this scoring system were proposed (Hubner et al., 2008), which enables morphological distinctions thus enabling a better grading of the disease. Using the modified scoring system, bleomycin induced lung fibrosis in rats was scored as follows: Grade 0 – normal lung, Grade 1 – isolated alveolar septa with gentle fibrotic changes, Grade 2 – knot like formation in fibrotic areas in alveolar septa, Grade 3 – contiguous fibrotic walls of alveolar septa, Grade 4 – single fibrotic masses, Grade 5 – confluent fibrotic masses, Grade 6 – large contiguous fibrotic masses, Grade 7 – air bubbles and Grade 8 – fibrotic obliteration. Further morphometric analysis can be conducted to quantify the total disease area (Nikota et al., 2017).</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Lungs are formalin fixed and paraffin embedded such that an entire cross section of lung can be presented on a slide. The entire cross section is captured in a series of images using wide field light microscope. Areas of alveolar epithelium thickening and consolidated air space are identified. ImageJ software (freely available) is used to trace the total area (green line) and the diseased area (red line) imaged and quantified. The diseased area is equal to disease area/total area (Nikota et al., 2017).</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><em>In vitro</em>, there is no single assay that can measure the alveolar thickness. However, a combination of assays spanning various KEs described above provide a measure of the extent of fibrogenesis potential of tested substances. Real-time reverse transcription-polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assays<strong><em> </em></strong>(ELISA) measuring increased collagen, Transforming growth factor beta 1 (TGF-β1) and various pro-inflammatory mediators are used as sensitive markers of potential of substances to induce the adverse outcome of lung fibrosis.</span></span></p>
UBERON:0002048lungHighUnspecificHighAdultsHighHighHigh<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">1. Ashcroft T, Simpson JM, Timbrell V. Simple method of estimating severity of pulmonary fibrosis on a numerical scale. J Clin Pathol. 1988 Apr;41(4):467-70. doi: 10.1136/jcp.41.4.467.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">2. Gracey DR, Divertie MB, Brown AL Jr. Alveolar-capillary membrane in idiopathic interstitial pulmonary fibrosis. Electron microscopic study of 14 cases. Am Rev Respir Dis. 1968 Jul;98(1):16-21. doi: 10.1164/arrd.1968.98.1.16.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">3. Hübner RH, Gitter W, El Mokhtari NE, Mathiak M, Both M, Bolte H, Freitag-Wolf S, Bewig B. Standardized quantification of pulmonary fibrosis in histological samples. Biotechniques. 2008 Apr;44(4):507-11, 514-7. doi: 10.2144/000112729. </span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">4. Koval M, Sidhaye VK. Introduction: The Lung Epithelium. In: Sidhaye VK, Koval M, editors. Lung Epithelial Biology in the Pathogenesis of Pulmonary Disease. Boston: Academic Press; 2017. p. xiii-xviii. Elsevier.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">5. Nikota J, Banville A, Goodwin LR, Wu D, Williams A, Yauk CL, Wallin H, Vogel U, Halappanavar S. Stat-6 signaling pathway and not Interleukin-1 mediates multi-walled carbon nanotube-induced lung fibrosis in mice: insights from an adverse outcome pathway framework. Part Fibre Toxicol. 2017 Sep 13;14(1):37. doi: 10.1186/s12989-017-0218-0. </span></span></p>
2017-07-26T19:13:542023-05-12T17:09:50Activation, Latent Transforming Growth Factor Beta 1TGFbeta1 activationMolecular2017-08-16T07:50:372017-08-16T07:50:37Activation, Transforming Growth Factor beta pathwayTGFbeta pathway activationMolecular2017-08-16T07:55:352017-08-16T07:55:35b1faec1c-da2a-4cbc-bc28-2806524368175e4f587d-311c-44bf-822e-ed2e7998a3cd<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Fibrosis by definition is the end result of a healing process. It involves a series of lung remodelling and reorganisation events leading to permanent alteration in the lung architecture and a fixed scar tissue or fibrotic lesion (Wallace WA, 2007). Excessive deposition of extracellular matrix (ECM) or collagen is the hallmark of this disease and there is ample evidence to support this KER (Fukuda 1985, Meyer 2017, Richeldi 2017, Thannickal 2004, Zisman<em> </em>2005).</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">By definition, pulmonary fibrosis is characterized by excessive deposition of ECM and destruction of native lung architecture (Fukuda 1985, Richeldi 2017, Thannickal 2004). Thus, the plausibility of this association is undisputed.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Excessive ECM deposition is the defining characteristic of pulmonary fibrosis, and the evidence to support this relationship is unequivocal. (Meyer 2017, Thannickal 2004, Zisman 2005).</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Since the adverse outcome of lung fibrosis involves multiple cell types, cell - cell interactions and cell–biomolecule interactions, it is difficult to recapitulate the entire process in one model. Therefore, an integrated approach, such as one consisting of cell systems that assess individual KEs and quantitative relationships between the KEs, is needed to predict the AO in humans.</span></span></p>
HighAdultHighHighHigh<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Humans (Meyer 2017, Zisman 2005), rats (Williamson 2015), mice (Williamson 2015).</span></span></p>
<ol>
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<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Fukuda Y, Ferrans VJ, Schoenberger CI, Rennard SI, Crystal RG. Patterns of pulmonary structural remodeling after experimental paraquat toxicity. The morphogenesis of intraalveolar fibrosis. Am J Pathol. 1985 Mar;118(3):452-75.</span></span></p>
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<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Meyer KC. Pulmonary fibrosis, part I: epidemiology, pathogenesis, and diagnosis. Expert Rev Respir Med. 2017 May;11(5):343-359. doi: 10.1080/17476348.2017.1312346.</span></span></p>
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<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Richeldi L, Collard HR, Jones MG. Idiopathic pulmonary fibrosis. Lancet. 2017 May 13;389(10082):1941-1952. doi: 10.1016/S0140-6736(17)30866-8. </span></span></p>
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<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Thannickal VJ, Toews GB, White ES, Lynch JP 3rd, Martinez FJ. Mechanisms of pulmonary fibrosis. Annu Rev Med. 2004;55:395-417. doi: 10.1146/annurev.med.55.091902.103810.</span></span></p>
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<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Wallace WA, Fitch PM, Simpson AJ, Howie SE. Inflammation-associated remodelling and fibrosis in the lung - a process and an end point. Int J Exp Pathol. 2007 Apr;88(2):103-10. doi: 10.1111/j.1365-2613.2006.00515.x.</span></span></p>
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<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Williamson JD, Sadofsky LR, Hart SP. The pathogenesis of bleomycin-induced lung injury in animals and its applicability to human idiopathic pulmonary fibrosis. Exp Lung Res. 2015 Mar;41(2):57-73. doi: 10.3109/01902148.2014.979516. </span></span></p>
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<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Zisman DA, Keane MP, Belperio JA, Strieter RM, Lynch JP 3rd. Pulmonary fibrosis. Methods Mol Med. 2005;117:3-44. doi: 10.1385/1-59259-940-0:003. </span></span></p>
</li>
</ol>
2017-07-26T19:19:192023-05-18T14:04:519236aaf7-361d-4e74-a81b-7cf4617cdf0e73754849-bee1-4719-adcc-436425f5bcfa2017-08-16T07:56:282017-08-16T07:56:2873754849-bee1-4719-adcc-436425f5bcfa06979adb-e535-4bf8-822d-b762f81e257a2017-08-16T07:57:352017-08-16T07:57:3573754849-bee1-4719-adcc-436425f5bcfa070d4a04-6eed-49e4-b110-39e8cac479a82017-08-16T07:58:462017-08-16T07:58:4606979adb-e535-4bf8-822d-b762f81e257ab1faec1c-da2a-4cbc-bc28-2806524368172017-08-16T07:59:152017-08-16T07:59:15070d4a04-6eed-49e4-b110-39e8cac479a8b1faec1c-da2a-4cbc-bc28-2806524368172017-08-16T07:59:462017-08-16T07:59:46Latent Transforming Growth Factor beta1 activation leads to pulmonary fibrosisLatent TGFbeta1 activation leads to pulmonary fibrosisUnder development: Not open for comment. Do not citeadjacentNot SpecifiedHighadjacentNot SpecifiedHighadjacentNot SpecifiedHighadjacentNot SpecifiedHighadjacentNot SpecifiedHighadjacentNot SpecifiedHighHigh<p>[1] Ehrhart F, Nymark P, Rieswijk L, Hanspers K, Mélius J: Lung fibrosis (Homo sapiens), http://wikipathways.org/index.php/Pathway:WP3624</p>
<p>[2] Vietti, G., Lison, D., & van den Brule, S. (2015). Mechanisms of lung fibrosis induced by carbon nanotubes: towards an Adverse Outcome Pathway (AOP). Particle and Fibre Toxicology, 13(1), 11. https://doi.org/10.1186/s12989-016-0123-y</p>
<p>[3] Labib, S., Williams, A., Yauk, C. L., Nikota, J. K., Wallin, H., Vogel, U., & Halappanavar, S. (n.d.). Nano-risk Science: application of toxicogenomics in an adverse outcome pathway framework for risk assessment of multi-walled carbon nanotubes. https://doi.org/10.1186/s12989-016-0125-9</p>
2017-07-26T18:54:432023-04-29T16:03:00